Gamma-hydroxy quaternary ammonium compounds



. 4nn r Patented Jan. 5, 1954 I OFFICE GAMMA-'HYDROXY QUATERNARY AMMONIUM COMPOUNDS" Everett-M. Schultz, Glenold'en;Pa.-,.assignor to Merck &-Co., -Inc.,.a..corporation of -New Jersey No D'rawing'; Applicationilway 9; 1951';

Serial No. 2255466 6 Claims. (Cl. 260-4943?) 1 Thisinvention' is: concerned with certain new chemical compounds. It is more particularly. concerned with the quaternary salts derived from gamma-hydroxy-tertiary. amines. The compounds of this inventioncan be representedv by the general formula 1 in which NA is a secondary amine'residue, R is chosen from the group consisting of lower alkyl, cycloaliphatic, aralkylyand aryl, R'is chosen from the group consistingoflower alkyl, aralkyl, allyl and cinnamyl and X is an-anion.

The starting materials for the compounds of this invention are gamma-hydroxy-tertiary amines the production ofwhich is'described in the application of James Sprague and Everett M. Schultz, Serial No. 151,044 filed'March 21, 1950, now abandoned. These gamma-hydroxytertiary amines are'prepared'by the hydrogenation, in the presence of platinum catalyst, of gamma-keto-tertiary amines inaqueous or alco holic solution.

In general, the compounds of this invention are prepared by reacting a gamma-hydroxy-tertiary amine with a quat'ernizin'g agent of the formula R'X in which R, has the meanings'heretofore described and Xis for example, hal'id'eormethylsulfate'. other than halide or methylsulfate can -be obtainedby means'of a procedure'hereinafter described. The gamma-hydroxy-tertiary"amine is ad'mixedwith the quaternizing agent, RX, with or: without a solvent and the reaction allowed to' proceed at room temperature. In general, the reactionis completedwithin 12to 24hours.

If the above reaction has been carried out without asolvent the reaction productis recrystallized from a-suitable solvent, such as ethanol, acetone, or ethylacetate or a solvent has been used purification is effected by one of two methods. If the solvent used is one in which the quaternary ammonium salt is insoluble the salt is separated by filtration and recrystallized as above. If, on the other hand, the solvent is one in which the'quaternary ammonium salt is soluble, such as, for example, methanol or ethanol, it is solvent by the addition of such as. benzene, ether, or

a. non-polar solvent,

ethyl acetate.

separated by filtration and recrystallized as above;

Compounds containing anions mixtures thereof. If

precipitated J from the The precipitated quaternary ammonium salt is" then The: compounds: of: this invention are illuse trated: by .such: compounds. as: 3-hydroxy-4- phenylhexyltrimethylammonium iodide, 3 hy.'- droxyiephenyle5 methylhexyltrimethylammoniumt iodide, 3-hydroxy-4-phenyl-5-methylhexyltrimethylammonium methylsulfate, 1.- (3 hydroxy-5 methyle i-phenylhexyl) -1-methylpiperi.- dinium iodide, l-benzyl-l-(3:-hydroxy-5'-methyl- 4 -phenylhexyl) piperidinium bromide, 1-ethy1- 1 (3 hydroxy 5-methyl-4-phenylhexyl) piperidinium iodide, 1 methyl-l-(3ehydroxy-4A diphenylbutyl) piperidinium iodide, 3;hydroxy-4,5,- diphenylamyltrimethylammoniumi iodide; 1- (425- diphenyl 3- hydroxyamyl)i-l-methylpiperidinium iodide, 4 cyclohexyl-3*hydroxyA-phenylbutyh trimethylammonium. iodide; 3-hydroxy-4+phenyleheptyltrimethylammonium methylsulfate:

It'is to be. understood thatthe'anion which occurs in. the foregoing compounds is not ofxpar ticular importance. to thephysiological: activity. Thus, a variety of anions can be substituted'for thoselistedabove and thephysiological activity of the compounds will remain; If one desires anions other than those listed above the compoundscan' be prepared conveniently by admixing the quaternary ammoniumzbromide or iodide. inwater's'olution' with silver oxide; There; will beobtained a precipitate of silver bromide: or iodide which can be removed by filtratonleaving a water solutionof'the'quaternary ammonium hydroxide. By'neutralization of this hydroxide with'an appropriate acid one can obtain the desired anion: For instance, if oneneutralizeswith phosphoric acidthere is obtained the quaternary ammonium phosphate; if one-neutralizes with sulfuric acid there is obtained the quaternary ammonium sulfateand'the like. In general, theanions derived frominorganic acids, the lower oarboxylic acids, and sulfonic acid are preferred.

The compounds of this. invention are useful in that they possess anticholinergic nature. possessing particular activity, 3-hydroxy-5 m e t by l 4 phenylhexyltrimethylammonium; iodide and methyl sulfate and l-(B-hydroxy -S- methyl 4 phenylhexyl) -1-methylpiperidinium iodideare ofiparticular. interest because of their high order of activity.

The compounds of this invention are illustrated. by but not. necessarily restricted .to, the followingv preferred embodiments:

Example 1.-Preparation of 3-hydrozcy-5- methyl 4 phenylhezcyltrimethylammonium i0 dide. 2:4 grams (0.01 mole) l-ph'enyl-l-isophysiological. activity of. an- Of the compounds.

3 propyl-4-dimethylamino-2 -butanol, was dissolved in 20 ml. ethyl ether and there was added 1.0 grams (0.05 mole) methyl iodide. The reaction mixture was allowed to stand at room temperature for approximately 2 hours. There was obtained a crystalline reaction product which was separated from the ether by filtration and recrystallized from approximately 10-15 ml. isopropyl alcohol. There was obtained 3.0 grams of 3-hydroxy-5-methyl-4-phenylhexyltrimethylammonium iodide, M. P. 15'l-8 C.

An aqueous solution of 3-hydroxy-5-methyl- 4-phenylhexyltrimethylammonium iodide was treated with excess silver oxide and stirred for approximately 30 minutes. The precipitated silver iodide and excess silver oxide were removed by filtration yielding an aqueous solution of the quaternary ammonium hydroxide. Portions of this solution were neutralized with phosphoric, acetic, sulfuric, p-toluenesulfonic and benzoic acids and the solutions evaporated to dryness. There were obtained 3-hydroxy-4-phenyl-5- methylhexyltrimethylammonium phosphate, acetate, sulfate, p-toluenesulfonate, and benzoate respectively. Neutralization of the quaternary ammonium hydroxide above prepared with any desired acid results in the introduction of acidic anion into the molecule.

Example 2.-Preparation of 1-(3-hydroxy-5- methyl 4 phenylhexyl)-1-methylpiperidinium iodide. 18.6 grams (0.06 mole) of l-isopropyl-lphenyl 4 (1-piperidyD-2-butanone hydrochloride (prepared by the reaction of 3-phenyl-4- methyl-Z-pentanone with paraformaldehyde and piperidine hydrochloride according to the Mannich reaction) was dissolved in 500 ml. water and there was added 0.9 gram Adams platinum oxide catalyst and the entire mixture was shaken under an atmosphere of hydrogen until the uptake of hydrogen ceased. This required approximately 24 hours. The catalyst was separated from the reaction mixture by filtration and the filtrate made basic with 20% sodium hydroxide solution. The oil that separated, l-isopropyl-lphenyl-4-(l-piperidyl)-2-butanol, was taken up in 250 ml. benzene and the benzene layer separated from the water layer. The benzene layer was washed 4 times with 100 ml. water. The benzene solution was dried by distilling ofi. approximately 100 ml. of benzene.

The benzene solution was allowed to cool and there was added 7.5 ml. methyl iodide and the mixture was allowed to stand at room temperature for approximately two days.

There was obtained a crystalline product which was separated from the benzene by filtration. The product was recrystallized from 220 ml. acetone. There was obtained 17.0 grams of 1-(3- hydroxy-5-methyl-4-phenylhexyl) l methylpiperidinium iodide, M. P. l501 C.

' Example 3.-Preparation of 4-cyclohexyl-3- hydroxy-4-phenylbutyltrimethyl-ammonium iodide. Following the procedure outlined in Example 1 and substituting for the amino butanol there used an equimolar quantity of l-phenyl-lcyclohexyl-4-dimethylamino-2-butanol there was obtained 4-cyclohexy1-B-hydroxy-4-phenylbutyltrimethylammonium iodide, M. P. 1'74.5-176 C.

Example 4.--Preparation of 3-hydroxy-4,5-diphenylamyltrimet hylammoniam iodide. Following the procedure outlined in Example 1 and substituting for the amino butanol there used an equimolar quantity of l-phenyl-l-benzyli-dimethylamino-2-butanol, there was obtained 3- hydroxy-4,5 diphenylamyltrimethylammonium iodide, M. P. 222-223 C.

Example 5.-Preparation of 3 hydroxy-stphenylhexyltrimethylammoniam iodide. Following the procedure outlined in Example 1 and substituting for the amino butanol there used an equimolar quantity of l-phenyl-l-ethyl-4-dimethylamino-2-butanol there was obtained 3- hydroxy-4-phenylhexyltrimethylammonium iodide, M. P. -l3'1 C.

Example 6.-Preparation of 1-methz/l-1-(3-hydroxy 4,4 diphenylbatyl) -piperidinium iodide. 3.7 grams (0.012 mole) 1,1-diphenyl-4-(1-piperidyl) -2 butanol was dissolved in 20 ml. of ethanol. There was added 8.5 grams (0.06 mole) of methyl iodide. A crystalline solid began to separate after approximately 5 minutes. The reaction mixture was chilled to approximately 5 C. and the ethanol removed by filtration. The crystalline product was recrystallized from approximately '70 m1. of a 4:1 methanol-water mixture. There was obtained l methyl 1 (3 hydroxy-4,4-diphenylbutyl) piperidinium iodide, M. P. 244-5 C.

Example 7.Preparatioh of 1-(4,5-dip'henyl-3- hydroxyamyl) 1 methyl piperidinium iodide.

Following the procedure outlined in Example 1 and substituting for the amino butanol there used an equimolar quantity of l-phenyl-l-benzyli- (l-piperidyD-Z-butanol, there was obtained 1- (4,5 diphenyl 3-hydroxyamyl) --l-methylpiperidinium iodide, M. P. 152 C.

Example fir-Preparation of 1-ethyl-1-(3-hydroxy 5 methyZ-4-phenylhexyl)-piperidinium iodide. Following the procedure outlined in Example 6 and substituting for the amino butanol there used an equimolar quantity of l-phenyl-lisopropyl-l-(l-piperidyl) -2-butanol and an equimolar quantity of ethyl iodide in place of the methyliodide there used there was obtained 1- ethyl-l-(3-hydroxy-5-methyl 4 phenylhexyl) piperidinium iodide, M. P. 142-3 C.

Example 9.Prepa1ation of 1-benzyl-1-(3-hydroxy-5-methyl 4 phenylhexyl) piperidinium bromide. Following the procedure outlined in Example 6 and substituting for the amino butanol there used an equimolar quantity of l-phenyl-lisopropyl-4-(l-piperidyl) 2 butanol and equimolar quantity of benzyl bromide for the methyl iodide there used, there was obtained an ethanol solution of the desired compound. There was added to the ethanol solution 5 volumes of ether and the product precipitated. The ether-ethanol was decanted off and to the residue there was added a quantity of water sufficient to dissolve r the compound at the boiling point of water. Up-- on cooling the water solution a crystalline material precipitates Which was separated from the water by filtration and recrystallized from a 4:1 (by volume) mixture of ethylacetate and isopropyl alcohol. There Was obtained l-benzyl-l- (3-hydroxy-5-methyl-4-phenylhexy1) piperidinium bromide, M. P. l23-8 C.

Example 10.Prepdration of 3-hydroxy- 5 methyl 4 phenylhexyltrimethylammonium methylsulfate. Following the procedure outlined n Example 1 and substituting for the methyl iodide there used an equimolar quantity of dimethylsulfate there was obtained 3-hydroxy-5- methyl 4 phenylhexyltrlmethylammonium methylsulfate, M. P. 1334 C.

Example 11.Prepav'ation of 3 hydroxg 4 phenylheptyltrimethylammoniam methylsulfate. Following the procedure outlined in Example 1 and substituting for the amino butanol there used an equimolar quantity of l-phenyl-l-n-propyl- 4-dimethylamino-Q-butanol and an equimolar quantity of dimethylsulfate for the methyl iodide there used, there was obtained 3-hydroxy-4- phenylheptyltrimethylammonium methylsulfate, M. P. 138.5-139.5 C.

It is to be realized that following the procedures of the foregoing examples any of the compounds of the general formula $1 R-OH(CH5)CH(OH)CHz-CH:1}IA

x can be prepared by using appropriate starting materials.

What is claimed is: 1. Compounds of the formula OH R in which R is chosen from the group consisting of lower alkyl, unsubstituted mononuclear alicyclic, mononuclear aralkyl hydrocarbon and mononuclear aryl hydrocarbon radicals; R is chosen from the group consisting of lower alkyl, mononuclear aralkyl hydrocarbon, allyl and cinnamyl, NA is chosen from the group consisting of a dilower alkyl amine and piperidine, and X is a non-toxic anion.

References Cited in the file Of this patent FOREIGN PATENTS Number Country Date 240,363 Switzerland May 16, 1946 265,665 Switzerland Apr. 1, 1950 OTHER REFERENCES Ruddy, Abstract of pap-er, meeting A. C. S., September 1946, pp. 14K-16K.

Adamson, J. Chem. Soc. (London), May 1949, part E, pp. 8144-5155.

Cunningham, J. Pharm. and Exp. Thera., June 1949, pp. 151-165.

Idson, Chem. Reviews, vol. 47 (December 1950), No. 3, DD. 513-515.

Lutz et al., J. Org. Chem. 12, 768 (1947). 

1. COMPOUNDS OF THE FORMULA 